Use of a combination of morphine and at least one opiate antagonist to treat opiate dependency and prevent non-oral opiate abuse among opiate addicts

ABSTRACT

The present invention relates to the use of an inseparable combination of morphine and at least one opiate antagonist with a bioavailability of less than 5% on oral administration for producing a medicament to be administered orally for treatment of opiate dependency in humans and to the use of an inseparable combination of an opiate and at least one opiate antagonists with a bioavailability of less than 5% on oral administration for producing a medicament to be administered orally for prevention of non-oral opiate abuse in opiate addicts.

The present invention relates to the use of a combination of morphineand at least one opiate antagonist, in particular naloxone, to treatopiate dependency in humans. The invention further relates to the use ofa combination of an opiate and at least one opiate antagonist to preventnon-oral opiate abuse among opiate addicts.

Drug addiction continues to be a problem in our society. It is commonknowledge that taking certain substances such as for example heroinleads to dependency. A distinction is made here between a physicaldependency and mental drug dependency (drug addiction). Physical drugdependency occurs when there is an abrupt cessation or significantreduction in the quantity of the substance taken. There are withdrawalsymptoms such as vomiting and cramps of the gastrointestinal tract. Adistinction is made between this and actual drug addiction, mentaldependency, which is regarded as a separate neurological disorder.Symptoms of drug addiction are a failure to control one's own use of thedrug, self-endangerment and a compulsive desire to acquire the drug.

By drug addiction within the scope of the present invention is meant inparticular an opiate dependency (mental and behavioural disorders due toopioids; F11 of ICD-10). A heroin dependency or opiate dependency can betreated particularly well with the present method.

Drug addiction is currently treated by switching the patient from adangerous drug to a less dangerous substitute, or reducing the patient'sdose under controlled conditions. However, for various reasons not everydrug is accepted by patients. Methadone, heroin, buprenorphine andmorphine are used as substitutes. Methadone is a synthetic opiate withthe formula:

Methadone has been used as a substitute since the 1960s, both in theoptically active L-form and in the racemate form. Methadone is suitablefor satisfactorily alleviating withdrawal symptoms, especially in heroinpatients. It has a longer-lasting effect than heroin, can be takenorally without any appreciable loss of effect and does not produce a“kick” (i.e. the especially euphoric feeling which is triggered e.g. byheroin and leads to drug addiction). In order to prevent an improperintravenous administration, methadone is often given in the form of asyrup mixed with sugar or orange juice in addiction treatmentprogrammes.

However, the effect of methadone differs from one individual to anotherand its administration is therefore not simple. Methadone also producesa high level of dependency. Methadone withdrawal symptoms actually lastlonger than those of heroin. Methadone, like all opiates, leads toconstipation, as it has a paralyzing effect on the gastrointestinalmusculature. In addition, methadone seems to have significantside-effects.

A dosage form with retarded morphine and retarded naloxone is known fromWO 97/33566 A2. This dosage form contains a semipermeable wall whichsurrounds a two-layered core consisting of an opioid (outer layer)and—separate from it—an antagonist (inner layer). The physicalseparation of the opioid and the antagonist means it is easy for thedrug addict to obtain the opioid through separation measures, forexample by first scraping off the outer wall of the dosage form and thenremoving the outer shell from the exposed core.

Controlled-release preparations based on retarded morphine and aretarded antagonist are known from WO 01/58447 A1. However, there is noindication that the antagonist is to have a low bioavailability.

Pain-therapy preparations based on retarded morphine and non-retardednaloxone are known from WO 99/32119 A1 and DE 43 25 465 A1, withoutaffecting the field of application of the present invention.

Combination preparations consisting of particular opioid analgesics andnaloxone are also known from the state of the art. The commercialproduct Talwin®Nx contains pentazocine and naloxone. The productValoron®N contains tilidine and naloxone. However, these are painkillersto which the naloxone is added to prevent improper use as a drug. Thusfar consideration has not been given to the use of these commercialproducts as drug substitutes. The emphasis in the state of the art hasbeen more on attempts to make it impossible to use the correspondingpreparations as drugs.

Furthermore, a combination of buprenorphine and naloxone is alreadyknown as a drug substitute. Because of the weak intrinsic activity ofthe substance, buprenorphine is suitable as a substitute for only someopiate addicts.

A need therefore exists for a different and improved drug-addictiontreatment.

According to the present invention it was surprisingly found that acombination of morphine and at least one opiate antagonist with abioavailability of less than 5% when administered orally represents asuitable substitute for the treatment of drug addiction. At the sametime non-oral abuse is reliably prevented.

The present invention therefore relates to the use of a non-separablecombination of morphine and at least one opiate antagonist with abioavailability of less than 5% when administered orally for thepreparation of a medicinal product to be administered only orally totreat drug addiction in humans, in particular for substitution therapyamong drug addicts.

However, the present invention also relates to the use of anon-separable combination of an opiate, preferably morphine, and atleast one opiate antagonist with a bioavailability of less than 5% whenadministered orally to prepare a medicinal product to be administeredonly orally to prevent non-oral opiate abuse among opiate addicts.

The substance combination according to the invention surprisinglyrepresents an ideal substitute. In the course of studies it was shownthat its receptor profile and its physiological degradation pathway areparticularly advantageous within the framework of a substitutiontherapy.

Abuse:

The substance combinations according to the invention prevent theirnon-oral abuse.

By non-oral abuse is meant intravenous, pulmonary (through smoking),nasal, sublingual or rectal abuse. In these cases the drug addictattempts to achieve the intoxicating effect by application paths notprovided for by the manufacturer of a corresponding preparation. Forexample a preparation is melted or dissolved and injected intravenouslyor a preparation is burnt on aluminium foil and the smoke inhaled(pulmonary abuse; foil smoking).

The selection according to the invention of antagonists having a lowbioavailability when applied orally, i.e. a bioavailability of less than5% when administered orally, and an agonist with a bioavailability thatis adequate for physiological blood levels when administered orally,ensures that the combination preparation according to the inventionleads to a good substitution result only if it is taken orally. If it istaken in other ways, for example by the intravenous, pulmonary, nasal orrectal route, where the first-pass metabolism through the liver and/ormetabolism in the intestinal wall and the cleavage activity of thedigestive enzymes are avoided, withdrawal symptoms occur directly, asthe antagonist takes full effect.

Non-Separability:

Many drug addicts split up the combination preparations with which theyare supplied within the framework of a substitution therapy, in order togain access to the respective intoxicating ingredient. To this end, inthe case of multilayered preparations they dissolve the individuallayers in solvent, for example ethanol, and obtain the pure addictivedrug by evaporating the thus-obtained solution. A manual separation alsotakes place, for example by scratching off or breaking open the outerenvelope of a preparation and exposing the addictive drugs inside. Theingredients of preparations which consist of individual recognizableunits, for example on the one hand tablets with the agonist and on theother hand tablets with the antagonist, can easily be separated fromeach other anyway.

As a result, a particular advantage of the present invention is that thepatient, i.e. the drug addict, cannot separate the morphine or moregenerally the opiate from the antagonist.

Administration forms suitable for this purpose are for example those inwhich agonist and antagonist are present as a powder or granule mixture.Suitable powders can have grain sizes of 25 μm to 0.1 mm, suitablegranules can have grain sizes of 0.1 mm to 2 mm (in each case themaximum size of all the particles present in the mixture). Determinationof the particle sizes can be carried out by separation methods, whereinsieve separation is particularly suitable. With this embodiment, becauseof the mixing and visual indistinguishability of the differentparticles, it is not possible for the drug addict to separate withcertainty the individual particles of the mixture into agonists andantagonists.

Administration forms in which agonist and antagonist are presentembedded together in a matrix and for example compressed into a tabletare also suitable. Here too it is no longer possible for the drug addictto separate the active ingredients from the matrix. The result ofdissolution in a solvent is that all the ingredients are equallydissolved and a separation with means available to the drug addict is nolonger possible. Nor does a mechanical division of the matrix containingthe active ingredients allow the agonist to be obtained separately fromthe antagonist.

In principle, in the present invention a non-separable administrationform of agonists and antagonists is chosen which does not allow aseparation of the mixture into agonists and antagonists by mechanicaland/or visual separation methods, i.e. for example by visual inspectionfollowed by manual separation of the different constituents of themixture, or by dissolving the mixture and then evaporating and/orprecipitating the individual constituents of the mixture.

An easy separability or solubility using physical or chemical methods,in particular simple household separation methods such as filteringthrough coffee filters, dissolution in easily accessible solvents,filtering through cigarette filters, straining, separation based ondifferent molecular weight and/or different floating properties(skimming) is thus prevented.

Opiate:

In principle, within the framework of the use according to the inventionfor the prevention of non-oral abuse, all known opiates can be used incombination with a corresponding antagonist countering the effect of theopiate. These include for example morphine, codeine, papaverine andthebaine. Morphine is particularly preferred.

Morphine is used within the framework of the use according to theinvention in the substitution therapy.

Morphine is an opiate with the formula:

Morphine, also colloquially called morphia, is a very effectivepainkiller which can be extracted from the seeds of the opium poppy.Just like heroin, it is addictive, but it is less effective.

According to the present invention morphine is administered in retardedor non-retarded form.

By a retarded form (or retard form) of a medicinal product is meant anadministration form in which the release of the active ingredient isslowed down. Using retarded forms, the active ingredient can be releasedin the body in a controlled manner and thus prevent possibly dangerousconcentration peaks of the active ingredient in the blood. Through thecontrolled release of the active ingredient, the medicinal product iseffective for longer in the patient. The active ingredient thereforeneeds to be taken less often.

According to the present invention a retarded form of morphine ispreferred. This can make it possible for the opiate to be taken onlyonce or twice daily.

Within the meaning of the present invention the terms “retarded form”,“retard form” and “sustained-release form” are used synonymously.

Through the use of morphine or more generally opiate in retarded form,the substitute needs to be taken less frequently. Because of thelonger-lasting effect of the morphine, the drug addict's need to obtaina fresh supply of intoxicants as soon as possible is alleviated. Inaddition, the dangers of an overdose are alleviated by the retard form,as the active ingredient is passed into the blood in a controlledmanner, avoiding concentration peaks.

Retarded forms of opiates and in particular of morphine are sufficientlyknown to a person skilled in the art. According to the present inventionevery retarded form of morphine and more generally opiate can be used.According to the present invention a formulation is preferred in whichthe morphine is adsorbed on a polymer, for example a hydrophilicpolymer, and embedded in a matrix, for example a hydrophobic matrix. Theantagonist is preferably also located in the matrix, in order to ensurethe non-separability according to the invention. The polymer ispreferably a cellulose polymer and the matrix a wax. On contact with thegastric juice the polymer forms a gel through which the activeingredient can pass only with a delay. Another preferred retardformulation is characterized in that, in a liquid administration form,the morphine is suspended in an ethyl cellulose polymer and releasedonly with a delay. Another common retard form is a tablet coated with aprotective layer. The protective layer dissolves only slowly in thegastric juice and the release of the active ingredient iscorrespondingly delayed.

The opiates, particularly the morphine, can be administered in all theusual administration forms according to the present invention.Physiologically acceptable salts such as hydrochlorides, hydrates,sulphates, chlorates and quaternary salts are preferred. Particularlypreferred morphine salts are morphine hydrochloride, morphine sulphatepentahydrate, morphine chlorate, morphine methobromide and otherquaternary morphine salts such as morphine-N-oxide.

The danger of the preparation according to the invention beingimproperly taken intravenously can also be further reduced by the opiatebeing present in retarded form.

The preparation according to the invention contains 1 to 2000 mg,preferably 100 mg to 1500 mg of opiate. The quantity can be adjustedaccording to the needs of the patient.

Antagonist:

According to the present invention the opiate is administered incombination with at least one antagonist. Naloxone or one of itsderivatives or salts is a preferred opiate antagonist. Naloxone has thefollowing structural formula:

The antagonist, in particular the naloxone, can be administered in allthe usual administration forms according to the present invention.Physiologically acceptable water-soluble salts such as hydrochloride orhydrochloride dihydrate are preferred. The antagonist is present in thepreparation according to the invention in either retarded ornon-retarded form. The non-retarded form is preferred.

Naloxone acts as an opiate antagonist in completely the opposite way toopiate agonists such as morphine: naloxone blocks the opiate receptorsand reduces the effect of the morphine. A correspondingly high dose ofnaloxone completely eliminates the effect of morphine, and there arewithdrawal symptoms. This effect is known and is exploited for exampleto treat opiate poisoning by administering naloxone.

Remarkably, naloxone has a significant antagonistic effect when it isadministered intravenously, but scarcely any when administered orally.The reason for this is that, when administered orally, naloxoneexperiences a pronounced first-pass metabolism and is therefore rapidlybroken down. In other words the bioavailability of orally administerednaloxone is very low, sometimes less than 5%, and the opioidal effect ofthe morphine is scarcely impaired by the naloxone. However, if takenintravenously or in some other improper way the naloxone would greatlyimpair the opioidal effect of the morphine. In other words, with thepreparation according to the invention, the patient is forced to takethe medicinal product orally. For drug addicts, the intravenous, nasalor pulmonary pathway is undoubtedly the administrative route of choice,because of the speed with which the effect (“kick”) sets in. With thepreparation according to the invention, the result of taking itintravenously would be merely frustration, however, as the effect of themorphine is greatly reduced by the intravenously effective naxolone, andin extreme cases even eliminated, which would lead to the immediateappearance of withdrawal symptoms.

The antagonists which can be used within the framework of the presentinvention have a bioavailability of less than 5%, preferably less than3%, particularly preferably less than 1%. By bioavailability is meant inthis case the percentage of the active ingredient which appearsunchanged in the blood when the mixture according to the invention isadministered orally. (The bioavailability of an intravenously injectedmedicinal product is by definition 100%. For a more detailed definition,reference is made to Rainer K. Liedtke, Worterbuch der KlinischenPharmakologie, Gustav Fischer Verlag, Stuttgart, N.Y., 1980.Bioavailability is also defined in WHO Annex 9, 1996.) The lowbioavailability ensures that a drug addict does not feel a “kick” whenhe takes the preparation according to the invention, but a relativelylow level of antagonists is maintained in the patient's blood. It issurprising in this connection that, despite the low bioavailability, asubstitution therapy with the advantages listed below is made possible.

According to the invention, at least one antagonist is used. The use ofone, two or three antagonists in combination with a correspondingopiate, preferably morphine, is preferred. The combination of morphineand naloxone is particularly preferred.

The possible combinations of retarded and non-retarded activeingredients comprise retarded morphine and non-retarded antagonists,retarded morphine and retarded antagonists, non-retarded morphine andnon-retarded antagonists as well as non-retarded morphine and retardedantagonists. Naloxone can be the preferred antagonist in each case.

According to the invention the quantity of antagonists in thepreparation is high enough to reduce the undesired side-effects causedby the morphine, for example constipation.

It was also shown that, due to the presence of naloxone, the patient'stolerance to morphine which would otherwise occur is reduced.

Thus the preparation according to the invention has the followingsurprising profile:

-   -   reduction or avoidance of the constipation caused by morphine;    -   reduction or avoidance of the development of morphine tolerance;    -   prevention of an improper intravenous, inhalational or nasal        intake (abuse);    -   excellent suitability as a substitute;    -   reduction or avoidance of the foul smell given off by        substituted patients, due to the constipation caused by        morphine;    -   reduction or avoidance of the sexual dysfunction triggered by        substitutes.

Moreover, the use according to the invention can contribute to areduction or avoidance of the change in the body mass index (BMI) aswell as a reduction or avoidance of the tooth decay which is to beobserved in patients prescribed a substitute.

According to the invention, 0.1 to 10 mg of naloxone, preferably 1 to 5mg of naloxone are contained per tablet per 100 mg of retarded morphine.

A particularly preferred embodiment of the present invention is apreparation with 100 mg to 1500 mg of retarded morphine in combinationwith 1 mg to 5 mg of naloxone.

Although naloxone is preferably used as an additional active ingredientaccording to the present invention, in principle all opiate antagonistswith a corresponding low bioavailability can be used when administeredorally. Such compounds are known to a person skilled in the art. Asregards quantity details and method of administration, what was saidabove concerning naloxone applies analogously to this substance.

The preparation according to the invention is characterized in that itcannot be taken intravenously, for the above reasons. The preparationaccording to the invention can be taken orally (e.g. as a solution ortablet). The corresponding administration forms are known to a personskilled in the art. Depending on the specific administration form, thepreparation according to the invention contains the additives customaryfor this, which are also sufficiently known to a person skilled in theart and require no further explanation here.

The invention is explained in more detail by the following exampleswithout being limited by them.

EXAMPLES

The morphine used in the following examples is a powder with a grainsize <400 μm; manufacturer: McFarland. The naloxone used is supplied bySanofi-Aventis and the Eudragit by Röhm GmbH, Darmstadt, Germany.

Example 1 Morphine/Naloxone Retard Capsules

The preparation of naloxone retard pellets and morphine retard pelletswhich are packed into a hard-gelatine capsule is described below:

Example 1A Naloxone-HCl Retard Pellets Formulation:

Ingredient Quantity/unit (mg) Quantity/batch (g) Naloxone HCl 2.0 33.3Eudragit RSPO 70.0 1166.7 Eudragit RLPO 8.0 133.3 Stearic acid 40.0666.7 Total 120.0 2000.0

Method:

Naloxone HCl, Eudragit RSPO, Eudragit RLPO and stearic acid are mixed ina twin-cylinder mixer. The mixed material is continuously introducedinto a twin-screw extruder and the resulting strands collected on aconveyor belt. The strands are cooled on the conveyor belt. The cooledstrands are cut into pellets in a pelletizer. The pellets are screenedand the desired screened portion collected.

Example 1B Morphine-HCl Retard Pellets Formulation:

Ingredient Quantity/Unit (mg) Quantity/batch (kg) Morphine HCl 12.0 3.2Eudragit RSPO 76.5 20.4 Ethyl cellulose 4.5 1.2 Stearyl alcohol 27.0 7.2Total 120.0 32.0

Method:

Stearyl alcohol flakes are passed through an impact grinding mill.Morphine HCl, Eudragit RSPO, ethyl cellulose and stearyl alcohol aremixed in a twin-cylinder mixer. The mixed material is continuouslyintroduced into a twin-screw extruder and the resulting strandscollected on a conveyor belt. The strands are cooled on the conveyorbelt. The cooled strands are cut into pellets in a pelletizer. Thepellets are screened and the desired screened portion collected.

The pellets prepared in Examples 1A and 1 B are packed into ahard-gelatine capsule in the ratio 1:1 and the latter is sealed.

Example 2 Opiate Agonist/Antagonist Retard Granules (Compressed intoTablets)

The preparation of retard tablets which contain morphine HCl andnaloxone HCl is described below, wherein both active ingredients arepresent as granules. The granules containing the morphine and thenaloxone are dispersed in a matrix with controlled release. The granulesare combined with molten wax (stearyl alcohol) in order to obtain waxedgranules which are then ground, mixed with other excipients andcompressed into tablets.

Formulation:

Ingredient Quantity/unit (mg) Quantity/batch (g) Morphine HCl 10.0 11.00Naloxone HCl 0.50 0.55 Spray-dried lactose 68.75 75.62 Povidone 5.005.50 Eudragit RS 30D (dry weight) 10.00 11.00 Triacetin 2.00 2.20Stearyl alcohol 25.00 27.50 Magnesium stearate 1.25 1.38 Opadry white5.00 5.50 Purified water 31.16* Total 127.5 140.25 *Remains only asresidual moisture in the product

Method:

Grinding: Eudragit is softened with triacetin by mixing and naloxone HCIis dissolved in this solution.Granulation: Morphine HCI, spray-dried lactose and povidone areintroduced into a fluidized-bed granulator and the solution prepared inthe preceding step is added.Grinding: The granules are passed through a rotating fan mill.Drying: If the moisture content of the granules is too high, they aredried.Waxing: The granules are waxed by addition of molten stearyl alcoholduring the mixing.Cooling: The waxed granules are cooled in a fluidized-bed drier.Grinding: The cooled and waxed granules are passed through a rotatingfan mill.Mixing: The ground and waxed granules are mixed with magnesium stearate.Pressing: The resultant granules are compressed using a tablet press.Coating: The opadry white is dispersed in purified water in order toobtain a coating solution which is applied to the tablet core.

Example 3 Hard-Gelatine Capsule Tablets with Opiate-Agonist/AntagonistExtrudates Formulation:

Ingredient Quantity/unit (mg) Quantity/batch (g) Morphine HCl 12.0120.00 Eudragit NE 30 D 76.0 760.0 Ethyl cellulose 4.5 45.0 Stearylalcohol 27.0 270.0 Naloxone HCl 0.5 5.0✓ Hard-gelatine capsule ✓ ✓ Total120.0 1200.0

1. A process of substitution therapy among opiate or heroin addictscomprising preparing a non-separable combination of morphine, or itsphysiologically acceptable salts, and at least one opiate antagonist, orits physiologically acceptable salts, wherein the opiate antagonist orits physiologically acceptable salts have a bioavailability of less than5% when the non-separable combination is administered orally, andadministering the non-separable combination only orally to the addicts.2. The process according to claim 1, further comprising alleviating orpreventing opiate-specific side-effects of the addicts administering thecombination to the addicts.
 3. The process according to claim 1,characterized in that the opiate antagonist comprises naloxone.
 4. Theprocess according to claim 1 wherein, the combination is selected fromthe group consisting of the morphine is retarded and the at least oneopiate antagonist is retarded, the morphine is retarded and the at leastone opiate antagonist is non-retarded, the morphine is non-retarded andthe at least one opiate antagonist is retarded, and the morphine isnon-retarded and the at least one opiate antagonist is non-retarded. 5.The process according to enema claim 1, characterized in that themorphine is adsorbed on a polymer and embedded in a matrix or themorphine is suspended in an ethyl cellulose polymer.
 6. The processaccording to claim 1, characterized in that the substitute therapy isadministered among heroin addicts.
 7. The process according to claim 1,characterized in that the combination is administered once or twicedaily.
 8. The process according to claim 1, characterized in that themorphine is used in the form of morphine hydrochloride or morphinesulphate pentahydrate.
 9. The process according to claim 3,characterized in that the naloxone is used in the form of naloxonehydrochloride or naloxone hydrochloride dihydrate.
 10. The processaccording to claim 1, characterized in that the combination contains 100mg to 2000 mg of retarded morphine.
 11. The process according to claim3, characterized in that the combination contains 0.1 to 10 mg ofnaloxone per 100 mg of retarded morphine.
 12. (canceled)
 13. The processof claim 1 wherein the combination comprises retarded morphine andnon-retarded naloxone present as a mixture of granules, wherein thegranules preferably have grain sizes of 0.1 mm to 2 mm.
 14. The processof claim 3, characterized in that the morphine comprises morphinesulphate pentahydrate and the naloxone comprises naloxone hydrochlorideor naloxone hydrochloride dihydrate.
 15. The process of claim 1 whereinthe opiate antagonist consists essentially of naloxone.
 16. A processfor prevention of non-oral opiate abuse among opiate addicts comprisingpreparing a non-separable combination of morphine, or itsphysiologically acceptable salts, and at least one opiate antagonist, orits physiologically acceptable salts, wherein the opiate antagonist orits physiologically acceptable salts have a bioavailability of less than5% when the non-separable combination is administered orally, andadministering the non-separable combination only orally to the addicts.17. A process for manufacturing a medicinal product for substitutiontherapy comprising preparing a non-separable combination of morphine, orits physiologically acceptable salts, and at least one opiateantagonist, or its physiologically acceptable salts, wherein the opiateantagonist or its physiologically acceptable salts have abioavailability of less than 5% when the non-separable combination isadministered orally.